Abstract:Single‐crystal X‐ray diffraction (SCXRD) is the preferred and most accurate technique for determining molecular structures. However, it can present challenges when dealing with specific small molecules and active pharmaceutical ingredients (APIs), as many do not form quality crystals without coformers or can be unstable. In this study, we introduce tetrakis(guanidinium) pyrenetetrasulfonate (G4PYR), a robust guanidinium‐organosulfonate (GS) framework that efficiently encapsulates small molecules and APIs rich in functional groups. The hydrogen bonding frameworks formed by G4PYR display well‐ordered structures with predictable pyrene‐pyrene distances, making them ideally suited for targeting arene‐based APIs with pendant groups. Successful encapsulation of various guests, including benzaldehyde, benzamide, and arenes containing multiple hydrogen bond donors and acceptors like uracil and thymine, was achieved. Furthermore, we successfully encapsulated important pharmaceutical and biologically relevant compounds, such as lidocaine, ropinirole, adenosine, thymidine, and others. Notably, we present a workflow for investigating host‐guest complex formation using powder X‐ray diffraction and high throughput experimentation.